US12268702B2 - Antitumor pharmaceutical composition comprising azvudine and chemotherapeutic agent - Google Patents

Antitumor pharmaceutical composition comprising azvudine and chemotherapeutic agent Download PDF

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US12268702B2
US12268702B2 US18/200,000 US202318200000A US12268702B2 US 12268702 B2 US12268702 B2 US 12268702B2 US 202318200000 A US202318200000 A US 202318200000A US 12268702 B2 US12268702 B2 US 12268702B2
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azvudine
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US20240293438A1 (en
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Pan Li
Limin JIA
Zhiyong QIN
Zhaoyang WANG
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Henan Genuine Biotech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention belongs to the field of medicines, and in particular to an antitumor pharmaceutical composition comprising azvudine.
  • DCK Deoxycytidine kinase
  • Azvudine is a broad-spectrum RNA virus inhibitor.
  • RdRp viral RNA-dependent RNA polymerase
  • azvudine triphosphate 5′-triphosphate metabolite
  • RdRp novel coronavirus polymerase
  • azvudine tablet was approved for marketing in China for the treatment of HIV-1 infected adult patients with high viral load.
  • azvudine was approved for the treatment of novel coronavirus infection.
  • Patent document CN201010506595.X discloses use of azvudine in the treatment of tumors, such as colon cancer, liver cancer, gastric cancer, esophageal cancer, lung cancer, breast cancer, cervical cancer, leukemia, and lymphoma. It has been found that azvudine has significant inhibitory effect on various human cancer cells and transplanted tumors in animals.
  • chemotherapeutic drugs currently used clinically have poor selectivity, which may cause great damage to normal tissues of the human body while treating tumor tissues, thereby leading to serious toxic and side effects.
  • Single drug therapy has defects such as poor physical and chemical properties, low bioavailability, and poor therapeutic effect. If chemotherapeutic drugs can be combined with azvudine, the anti-tumor effect can be improved. Based on the complementary synergy between the anti-tumor mechanisms of the two drugs, synergistic enhancement of anti-tumor efficacy with chemotherapy and immunity can be achieved by double-targeting tumor cells.
  • the present disclosure provides a pharmaceutical composition comprising azvudine (FNC) and a chemotherapeutic agent, and use of the pharmaceutical composition in the manufacture of a medicament for preventing or treating a tumor disease.
  • FNC azvudine
  • the pharmaceutical composition of the present invention has the following advantages:
  • the present invention provides a pharmaceutical composition, comprising:
  • the chemotherapeutic agent is selected from the group consisting of capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clofazimine, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin, paclitaxel, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, folinic acid, doxorubicin liposome, daunorubicin liposome, lomustine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paliittazine, pemetrexed, pen
  • the chemotherapeutic agent is selected from the group consisting of capecitabine, cyclophosphamide, dacarbazine, paclitaxel and a combination thereof.
  • the present invention further provides another pharmaceutical composition, comprising:
  • the (i) and (ii) are administered simultaneously, separately, or sequentially, or the (i) and (ii) exist in the same dosage form.
  • the pharmaceutical composition is used for treating a tumor-related disease.
  • the tumor-related disease is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, bone tumor, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureter tumor, bladder tumor, gallbladder cancer, non-small cell lung cancer, cholangiocarcinoma and choriocarcinoma.
  • the azvudine is administered at an amount selected from 1-100 mg, and the chemotherapeutic agent is administered at an amount selected from 1-500 mg.
  • the azvudine is administered at an amount selected from 1-100 mg, and the avastin is administered at an amount selected from 1-500 mg.
  • the azvudine is administered at an amount selected from the group consisting of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg
  • the chemotherapeutic agent is administered at an amount selected from the group consisting of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg,
  • the azvudine is administered at an amount selected from 1-100 mg, and at a frequency of once a day, twice a day or three times a day
  • the chemotherapeutic agent is administered at an amount selected from 1-500 mg, and at a frequency of once a day, twice a day or three times a day.
  • the azvudine is administered at an amount selected from 1-50 mg, and at a frequency of once a day or twice a day, and the chemotherapeutic agent is administered at an amount selected from 1-100 mg, and at a frequency of once a day.
  • the azvudine is administered at an amount selected from 1-20 mg, and at a frequency of once a day or twice a day
  • the chemotherapeutic agent is administered at an amount selected from 1-40 mg, and at a frequency of once a day.
  • the azvudine is administered at an amount selected from 1-10 mg, and at a frequency of once a day or twice a day
  • the chemotherapeutic agent is administered at an amount selected from 1-10 mg, and at a frequency of once a day.
  • the chemotherapeutic agent is administered at an amount selected from the group consisting of 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg and 50 mg, and at a frequency of once a day or twice a day.
  • the chemotherapeutic agent is administered at an amount selected from 10 mg, 20 mg, 40 mg and 60 mg, and at a frequency of once a day.
  • the azvudine is administered at an amount selected from the group consisting of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg and 20 mg, and at a frequency of once a day or twice a day.
  • the azvudine is administered at an amount selected from the group consisting of 1 mg, 2 mg, 4 mg and 6 mg, and at a frequency of once a day.
  • the chemotherapeutic agent is administered at an amount selected from the group consisting of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg and 10 mg, and at a frequency of once a day or twice a day.
  • the chemotherapeutic agent is administered at an amount selected from the group consisting of 10 mg, 20 mg, 40 mg and 60 mg, and at a frequency of once a day.
  • the chemotherapeutic agent is administered at an amount selected from the group consisting of 1 mg, 2 mg, 4 mg, 6 mg and 8 mg, and at a frequency of once a day or twice a day.
  • the chemotherapeutic agent is administered at an amount selected from the group consisting of 1 mg, 2.5 mg, 5 mg and 10 mg, and at a frequency of once a day.
  • Route of the combined administration in the present invention is selected from the group consisting of oral administration, parenteral administration and transdermal administration, wherein the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection and intramuscular injection, preferably oral administration.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above azvudine and chemotherapeutic agent and one or more pharmaceutically acceptable carriers, excipients and diluents.
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, it can be formulated into a tablet, a capsule, a pill, a granule, a solution, a suspension, a syrup, an injection (including an injection solution, a sterile powder for injection and a concentrated solution for injection), a suppository, an inhalant or a spray.
  • the pharmaceutical composition can also be made into the same dosage form, for example, the azvudine and chemotherapeutic agent can be formulated into a composite tablet, a composite capsule, a composite pill, a composite granule, a composite solution, a composite suspension, a composite syrup, a composite injection (including an injection solution, a sterile powder for injection and a concentrated solution for injection), a composite suppository, a composite inhalant or a composite spray.
  • the azvudine and chemotherapeutic agent can be formulated into a composite tablet, a composite capsule, a composite pill, a composite granule, a composite solution, a composite suspension, a composite syrup, a composite injection (including an injection solution, a sterile powder for injection and a concentrated solution for injection), a composite suppository, a composite inhalant or a composite spray.
  • the present invention further provides a method for treating a tumor disease, comprising administering an effective amount of the above azvudine and an effective amount of the above chemotherapeutic agent to a subject in need thereof.
  • the present invention further provides a pharmaceutical kit for use in a medicament for treating a tumor disease, which comprises the pharmaceutical composition of azvudine and chemotherapeutic agent described in the present disclosure.
  • azvudine is administered in combination with a chemotherapeutic agent, thereby enhancing the effect of drugs for treating a tumor disease.
  • the “combination” described in the present invention is a mode of administration that refers to the administration of at least one dose of azvudine and at least one dose of chemotherapeutic agent within a certain period of time, wherein both substances show pharmacological effects.
  • the period of time can within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours.
  • the azvudine and chemotherapeutic agent can be administered simultaneously or sequentially. Such a treatment that azvudine and a chemotherapeutic agent are administered by the same route of administration or by different routes of administration is included in this period of time.
  • FIG. 1 shows the effects of azvudine and capecitabine used alone or in combination on the subcutaneous xenograft tumor volume in human colon cancer COLO 205 tumor model.
  • FIG. 2 shows the effects of azvudine and capecitabine used alone or in combination on the subcutaneous xenograft tumor volume in human colorectal cancer LoVo tumor model.
  • FIG. 3 shows the effects of azvudine and cyclophosphamide used alone or in combination on the subcutaneous xenograft tumor volume in human Burkitt's lymphoma cells Daudi tumor model.
  • FIG. 4 shows the effects of azvudine and cyclophosphamide used alone or in combination on the subcutaneous xenograft tumor volume in human acute lymphoblastic leukemia cell MOLT4 tumor model.
  • FIG. 5 shows the effects of azvudine and paclitaxel used alone or in combination on the subcutaneous xenograft tumor volume in human ovarian cancer OVCAR-8 tumor model.
  • FIG. 6 shows the effects of azvudine and avastin used alone or in combination on the subcutaneous xenograft tumor volume in human ovarian cancer OVCAR-8 tumor model.
  • FIG. 7 shows the effects of azvudine and dacarbazine used alone or in combination on the subcutaneous xenograft tumor volume of human melanoma A2058 tumor model.
  • mice were 68 (48 plus 20 spare mice) BALB/c female nude mice, 7-8 weeks old (the age of mice at the time of tumor cell inoculation) and weighing 15.7-20.7 g, which were purchased from Beijing VitalRiver Experimental Animal Technology Co., Ltd. Breeding environment was SPF grade. The experimental animals were all kept in an independent ventilated box with constant temperature and humidity. The temperature of the breeding room was 20-26° C., the humidity was 40-70%. The breeding room was ventilated 10-20 times per hour. The alternating time of day and night was 12 h/12 h. The mice were continuously supplied with cobalt 60 radiation sterilized mouse complete pellet feed, and had free access to the feed.
  • mice drank tap water (available after sterilization with high-pressure steam), which was continuously supplied using a water-drinking bottle, and had free access to water.
  • the mouse box was a polysulfone mouse box, which was used after sterilization under high pressure, with a size of 325 mm ⁇ 210 mm ⁇ 180 mm.
  • Colo 205 cells were cultured in RPMI1640 medium containing 10% fetal bovine serum. Colo 205 cells in the exponential growth phase were collected, resuspended in PBS to an appropriate concentration and mixed with Matrigel at a ratio of 1:1. The resulting mixture was used for subcutaneous inoculation of tumor in mice. 5 ⁇ 10 6 Colo 205 cells were subcutaneously inoculated on the right side of female mice. The day of inoculation was defined as Day 0. When the average tumor volume reached 110.26 mm 3 , the mice were randomly divided into groups according to tumor size.
  • Relative tumor proliferation rate refers to the percentage value of the relative tumor volume or tumor weight of the treatment group and the control group at a certain time point, which was calculated as follows:
  • the capecitabine 400 mg/kg treatment group had an average tumor volume of 264.96 mm 3 , which had statistically significant difference compared with the control group (p ⁇ 0.001), with a relative tumor inhibition rate TGI (%) of 81.93%.
  • the combination group of azvudine 1 mg/kg and capecitabine 400 mg/kg had an average tumor volume of 144.76 mm 3 , which had statistically significant difference compared with the control group (p ⁇ 0.001), with a relative tumor inhibition rate TGI (%) of 90.14%.
  • Human colon cancer cells LoVo (Cat. No.: ECACC-87060101) were cultured in vitro as a monolayer in F12K medium containing 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, in a 37° C. and 5% CO 2 incubator. The cells were routinely digested with trypsin-EDTA and passaged twice a week. When the cell saturation reached 80%-90% and the cell number achieved the requirement, the cells were collected, counted and inoculated.
  • LoVo cells 0.1 mL (10 ⁇ 10 6 ) of LoVo cells were subcutaneously inoculated on the right back of each mouse. The grouping administration was started when the average tumor volume reached about 147 mm 3 .
  • the tumor volume changes and the tumor weight changes in each group (on the 21 st day of administration) after administration of test drugs for treating BALB/c nude mice with Lovo cell subcutaneous xenograft tumor are shown in Table 5 and Table 6 respectively.
  • the in vivo efficacy of the test drugs in the LoVo xenograft tumor model was evaluated.
  • the tumor volume and tumor weight of each group on the 21 st day of administration are shown in Table 5, Table 6 and Table 2, respectively.
  • the tumor volume of the tumor-bearing mice in the blank control group reached 1481 mm 3 .
  • the test drug azvudine (1 mg/kg) group showed a small tumor inhibitory effect, with a tumor volume of 902 mm 3 , T/C of 62.00%, TGI of 43.40%, and p-value of 0.086.
  • test drug capecitabine (400 mg/kg) group showed a small tumor inhibitory effect, with a tumor volume of 919 mm 3 , T/C of 60.94%, TGI of 42.11%, and p value of 0.696.
  • the test drugs combination group of azvudine+capecitabine (1+400 mg/kg) showed a significant tumor inhibitory effect, with a tumor volume of 676 mm 3 , T/C of 48.18%, TGI of 60.29% and p-value of 0.282.
  • the combined administration of azvudine+capecitabine can improve the antitumor effect of single drug capecitabine in the LoVo colorectal tumor, and can increase TGI from 42.1% to 60.3%.
  • Human Burkitt's lymphoma cells Daudi (Cat. No.: DSMZ-ACC129) were in vitro suspended and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 2 mM glutamine, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, in a 37° C. and 5% CO 2 incubator. When the cell saturation achieved 80%-90% and the cell number reached the requirement, the cells were collected, counted and inoculated.
  • 0.2 mL (10 ⁇ 10 6 ) of Daudi cells were subcutaneously inoculated on the right back of each mouse. The grouping administration was started when the average tumor volume reached about 100 mm 3 .
  • the in vivo efficacy of the test drugs in the Daudi xenograft tumor model was evaluated.
  • the tumor volumes of each group at different time points are shown in Table 8 and Table 9.
  • the tumor volume of the tumor-bearing mice in the blank control group reached 2,895 mm 3 .
  • the test drug azvudine (1 mg/kg) group showed a significant tumor inhibitory effect, with a tumor volume of 909 mm 3 , T/C of 30.64%, TGI of 71.09% and p-value of ⁇ 0.0001.
  • the test drug cyclophosphamide (50 mg/kg) showed a significant tumor inhibitory effect, with a tumor volume of 263 mm 3 , T/C of 8.83%, TGI of 94.17% and p value of ⁇ 0.0001.
  • the test drugs combination group of azvudine+cyclophosphamide (1+50 mg/kg) showed a significant tumor inhibitory effect, with a tumor volume of 13 mm 3 , T/C of 0.42%, TGI of 103.15%, and p-value of ⁇ 0.0001.
  • test drugs azvudine (1 mg/kg) in combination with cyclophosphamide can improve the tumor inhibitory effect of single drug CTX in the human Burkitt's lymphoma cell Daudi, and increase TGI from 94.17% to 103.15%.
  • MOLT4 Human acute lymphoblastic leukemia cells
  • MOLT4 Cat. No.: ECACC-85011413
  • RPMI 1640 medium containing 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, in a 37° C. and 5% CO 2 incubator.
  • the cell saturation achieved 80%-90% and the cell number reached the requirement, the cells were collected, counted and inoculated.
  • MOLT4 cells 0.2 mL (10 ⁇ 10 6 ) were subcutaneously inoculated on the right back of each mouse. The grouping administration was started when the average tumor volume reached about 148 mm 3 .
  • Tumor weight on the 28 th day of administration Tumor weight (g) T/C weight Group (On the 28 th day) (%) p value
  • Vehicle 2.971 ⁇ 0.228 — — Azvudine (1 mg/kg) 1.168 ⁇ 0.145 39.31 ⁇ 0.0001
  • Cyclophosphamide 0.822 ⁇ 0.065 27.65 ⁇ 0.0001 (50 mg/kg) Azvudine + 0.344 ⁇ 0.050 11.56 ⁇ 0.0001 Cyclophosphamide (1 + 50 mg/kg)
  • the in vivo efficacy of the test drugs in the MOLT4 xenograft tumor model was evaluated.
  • the tumor volumes of each group at different time points are shown in Table 10 and Table 11.
  • the tumor volume of the tumor-bearing mice in the blank control group reached 2,896 mm 3 .
  • the test drug azvudine (1 mg/kg) group showed a tumor inhibitory effect, with a tumor volume of 979 mm 3 , T/C of 33.89, TGI of 69.73%, and p-value of ⁇ 0.0001.
  • cyclophosphamide CTX (50 mg/kg) group showed a significant tumor inhibitory effect, with a tumor volume of 716 mm 3 , T/C of 24.53%, TGI of 79.34%, and p value of ⁇ 0.0001.
  • the test drugs combination group of azvudine+cyclophosphamide (1+50 mg/kg) showed a significant tumor inhibitory effect, with a tumor volume of 253 mm 3 , T/C of 8.75%, TGI of 96.14%, and p-value of ⁇ 0.001.
  • the analysis and statistical results of the tumor weight in the test drugs combination group were basically consistent with the tumor volume data.
  • test drugs azvudine (1 mg/kg), cyclophosphamide (50 mg/kg) and azvudine+cyclophosphamide (1+50 mg/kg) under test doses had significant inhibitory effect on the growth of MOLT4 xenograft tumor.
  • test substances azvudine (1 mg/kg) in combination with cyclophosphamide can improve the tumor inhibitory effect of single drug cyclophosphamide in MOLT4 human acute lymphoblastic leukemia tumor, and increase TGI from 79.34% to 96.14%.
  • OVCAR-8 cells were cultured in RPMI1640 medium containing 10% fetal bovine serum. OVCAR-8 cells in the exponential growth phase were collected, resuspended in PBS to an appropriate concentration and mixed with Matrigel at a ratio of 1:1. The resulting mixture was used for subcutaneous inoculation of tumor in mice.
  • Relative tumor proliferation rate refers to the percentage value of the relative tumor volume or tumor weight of the treatment group and the control group at a certain time point, which was calculated as follows:
  • T and C are the relative tumor volumes (RTV) or tumor weights (TW) of the treatment group and the control group at a specific time point).
  • the tumor volume of the vehicle control group was 558.68 mm 3 .
  • the combined administration of the test drugs azvudine and paclitaxel significantly improved the anti-tumor effect of single drug paclitaxel (with a TGI of 26.5%).
  • the combined administration of test drugs azvudine and avastin significantly improved the antitumor effect of single drug avastin (with a TGI of 17.70%).
  • the tumor growth of each treatment group and control group is shown in Table 12.
  • Human melanoma cells A2058 (Cat. No.: CRL-11147) were cultured in vitro as a monolayer in DMEM medium containing 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, in a 37° C. and 5% CO 2 incubator. The cells were routinely digested with trypsin-EDTA and passaged twice a week. When the cell saturation reached 80%-90% and the cell number achieved the requirement, the cells were collected, counted and inoculated.
  • 0.2 mL (5 ⁇ 10 6 ) of A2058 cells were added with Matrigel, and the mixture was subcutaneously inoculated on the right back of each mouse. The grouping administration was started when the average tumor volume reached about 136 mm 3 .
  • the in vivo efficacy of the test drugs in the A2058 xenograft tumor model was evaluated.
  • the tumor volumes of each group at different time points are shown in Table 13.
  • the tumor volume of the tumor-bearing mice in the blank control group reached 2724 mm 3 .
  • the test drug azvudine (1 mg/kg) group showed a small tumor inhibitory effect, with a tumor volume of 2253 mm 3 , T/C of 79.67%, TGI of 18.22%, and p value of 0.518.
  • the test drugs combination group of azvudine+dacarbazine (1+60 mg/kg) showed a significant tumor inhibitory effect, with a tumor volume of 910 mm 3 , T/C of 31.52%, TGI of 70.07%, and p-value of ⁇ 0.001.

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